Treating diabetic inflammation using AMP-activated protein kinase activators
Zhang, J
Date: 29 January 2024
Thesis or dissertation
Publisher
University of Exeter
Degree Title
PhD in Medical Studies
Abstract
Diabetes mellitus (DM) is a global public health problem. Increasing evidence has shown that
chronic low-grade inflammation contributes to the pathogenesis of diabetes and its associated
complications. The primary symptom of diabetes, hyperglycaemia, and a common complication
in insulin-treated diabetes, hypoglycaemia, both promote ...
Diabetes mellitus (DM) is a global public health problem. Increasing evidence has shown that
chronic low-grade inflammation contributes to the pathogenesis of diabetes and its associated
complications. The primary symptom of diabetes, hyperglycaemia, and a common complication
in insulin-treated diabetes, hypoglycaemia, both promote pro-inflammatory responses, although
the mechanism remains not fully understood. It has also been revealed that metabolism is
associated with inflammatory responses in immune cells. However whether targeting
metabolism could serve as a potential therapeutic approach to alleviate diabetic inflammation
remains unknown. This study focused on AMP-activated protein kinase (AMPK), a key regulator
of metabolism, to explore its involvement in the regulation of inflammatory response in
macrophages.
In both peripheral macrophages and central macrophages, microglia, low glucose enhanced the
release of a pro-inflammatory cytokine, macrophage migration inhibitory factor (MIF), which
has been observed to be elevated in people with diabetes and represents the severity of the
disease. Importantly, the MIF release from macrophages was significantly suppressed by
pharmacological AMPK activation. A similar trend was also noted in macrophages from mice
with genetic activation using AMPKγ1 gain-of-function (D316A). These results suggest an anti-inflammatory role of AMPK during hypoglycaemia. Additionally, macrophages exposed to low
glucose showed a transient activation of AMPK and metabolic adaptation with an increased ratio
of oxidative phosphorylation to glycolysis to maintain ATP levels. However, this metabolic
adaptation was significantly attenuated by potent pharmacological AMPK activation in short term though the ATP levels were not altered. Furthermore, pharmacological AMPK activation
did not alter either autophagy or low glucose-induced oxidative stress in macrophages.
Nevertheless, AMPK activation modestly reduced low glucose-induced nuclear translocation of
NFĸB signalling and the inhibition of NFĸB signalling diminished low glucose-induced MIF release.
This evidence suggests that the inhibitory effect of AMPK on low glucose-induced MIF release is
mediated, at least in part, by limiting NFĸB signalling. Compared to peripheral macrophages,
microglia displayed earlier elevation of MIF release and earlier cell death, suggesting increased
vulnerability to low glucose-induced metabolic stress. Given that glucose is the major energy
source in the brain, the protective role of pharmacological AMPK activation in microglia during
hypoglycaemia is particularly important. Collectively, these findings confirmed the hypothesis,
highlight the anti-inflammation role of AMPK in macrophages/microglia during low glucose
exposure and suggest that pharmacological AMPK activation may be a novel strategy for
combating inflammation in hypoglycaemia.
3
AMPK is a heterotrimeric complex, consisting of three subunits: α, β and γ subunits. Each subunit
has two (α subunit and β subunit) or three (γ subunit) isoforms. Previous studies have suggested
that different compositions of AMPK subunit isoforms may be involved in physiological or
pathological processes, and AMPK isoforms exhibit distinct tissue-specific expression patterns
that vary across species. Consequently, the pharmacological properties of AMPK activators may
differ due to their isoform selectivity or bias. However, the distributions of AMPK isoforms in
different tissues/species remain not fully elucidated. In this study, RNA-seq data analysis using
open-source data (Gene Expression Omnibus) was performed to identify the composition of
AMPK subunit isoforms expressed in various tissues across three species; mouse, rat and human.
The in-sample abundance analysis revealed tissue and species differences in AMPK isoenzymes
expressed. Furthermore, RNA-seq data analysis demonstrated that the abundance of AMPKα1
was increased along with a decrease in AMPKα2 expression in diabetic kidney, brain and skeletal
muscle but not in other tested tissues. Additionally, stimulation with lipopolysaccharide (LPS)
increased the percentage of AMPK γ1 expressed in macrophages/microglia. The mechanisms
and physiological implications of these changes in the composition of AMPK subunit isoforms
remain unclear. Nevertheless, these findings pave the way for future research elucidating the
isoform-specific functions of AMPK and encouraging the development and application of AMPK
activators/inhibitors with isoform selectivity.
Doctoral Theses
Doctoral College
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